1. ¹Gene Therapy Research Unit/Cell Biology Laboratory, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon 305-333, Republic of Korea
2. ²Samyang Genex Biotech Research Institute, Daejeon, Republic of Korea

Correspondence: Dong-Soo Im, Fax: +82 42 860 4597. E-mail: imdongsu@kribb.re.kr

Received 24 May 2004; Accepted 19 July 2004.

Abstract

Solid tumors contain normoxic and hypoxic regions depending on the distance from the capillary. Normal cells may also be exposed to hypoxia under certain physiological conditions. Tumor hypoxia has been shown to associate strongly with tumor propagation and malignant progression. Hypoxia-inducible factor (HIF)-1 is stable under hypoxia and induces transcription of target genes by binding to the hypoxia-response element (HRE). Here we investigated the oncolytic effects of a novel adenovirus mutant with a deleted E1B55 gene (Ad.55.HRE), in which the expression of E1A, which is essential for adenoviral replication, is regulated under the control of an HRE-expression system. Ad.55.HRE expressed E1A under normoxia and more E1A under hypoxia and exhibited oncolytic effects on various cultured tumor cells, but its cytotoxic effect is relatively attenuated in normal fibroblast cells under normoxic and hypoxic conditions. Ad.55.HRE lysed Huh-7 hepatoma cells stably expressing HIF-1 more effectively compared to parental cells. Ad.55.HRE treatment exhibited significant antitumor activity in PC-3 prostate- and MDA-MB-435 breast tumor-bearing nude mice in which HIF-1 protein was immunohistochemically detected. The E1A and hexon proteins of adenovirus were immunostained in MDA-MB-435 xenografts after Ad.55.HRE treatment, suggestive of viral replication. Our results suggest that Ad.55.HRE may be useful for the treatment of solid tumors.